CAPACITY: A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH

Sponsor

United Therapeutics (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04084678

Collaborator

(none)

193

Enrollment

Locations

Arms

34.1

Anticipated Duration (Months)

5.2

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Study ROR-PH-302, ADVANCE CAPACITY, is designed to evaluate the effects of ralinepag therapy on exercise capacity as assessed by change in peak oxygen consumption (VO2) derived from cardiopulmonary exercise testing (CPET) after 28 weeks of treatment

Condition or Disease	Intervention/Treatment	Phase
PAH Pulmonary Hypertension Hypertension Connective Tissue Disease Familial Primary Pulmonary Hypertension Vascular Diseases Cardiovascular Diseases Hypertension, Pulmonary Lung Diseases Respiratory Tract Disease Pulmonary Arterial Hypertension	Drug: Ralinepag Drug: Placebo	Phase 3

Detailed Description

ROR-PH-302 is a 28-week multicenter, randomized, double-blind, placebo-controlled study. Subjects who meet entry criteria will be randomly allocated 2:1 to receive ralinepag or placebo, in addition to their PAH-specific background therapy, as applicable. The primary endpoint is change from Baseline in peak VO2 (assessed by CPET) at Week 28. All subjects who complete the study on study drug through Week 28 will have the option to receive ralinepag in an open-label extension (OLE) study. Subjects who discontinue study drug prior to Week 28, as well as those who complete Week 28 on study drug but choose not to participate in the OLE study, will be contacted every 6 months and at the end of the study to determine their survival status. Subjects who prematurely discontinue study drug or withdraw from the study for any reason will not be eligible to enter the OLE study.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

193 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Ralinepag to Evaluate Safety and Effects on Exercise Capacity Assessed by CPET in Subjects With WHO Group 1 Pulmonary Hypertension Who Recently Initiated Therapy

Actual Study Start Date :

Oct 29, 2020

Anticipated Primary Completion Date :

Sep 1, 2023

Anticipated Study Completion Date :

Sep 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ralinepag Ralinepag once daily extended-release tablets (oral) 50, 250, and 400 mcg titrated to the individual maximum tolerated dose (maximum dose of 1400 mcg)	Drug: Ralinepag Oral ralinepag Other Names: APD811
Placebo Comparator: Placebo Matching placebo tablets (oral)	Drug: Placebo Matching oral tablets

Arm

Intervention/Treatment

Experimental: Ralinepag

Ralinepag once daily extended-release tablets (oral) 50, 250, and 400 mcg titrated to the individual maximum tolerated dose (maximum dose of 1400 mcg)

Drug: Ralinepag

Oral ralinepag

Other Names:

APD811

Placebo Comparator: Placebo

Matching placebo tablets (oral)

Drug: Placebo

Matching oral tablets

Outcome Measures

Primary Outcome Measures

Change from Baseline in peak VO2 assessed by CPET [Baseline to Week 28]
Peak VO2 by CPET was measured at Baseline (prior to starting study drug) and Week 28

Secondary Outcome Measures

Change from Baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) [Baseline to Week 28]
NT-proBNP was measured at Baseline (prior to starting study drug) and Weeks 4, 8, 12, 16, 20, 24 and 28
Change from Baseline in Minute Ventilation (VE)/Carbon Dioxide output (VCO2) slope [Baseline to Week 28]
VE/VCO2 slope (from CPET) was calculated at Baseline (prior to starting study drug) and Week 28
Change from Baseline in health-related quality of life measured by the Short Form Health Survey (SF-36) Scores [Baseline to Week 28]
SF-36 was assessed at Baseline (prior to starting study drug) and Weeks 16 and 28. The SF-36 consisted of 36 questions in 8 health categories (Vitality, Physical Functioning, Bodily Pain, General Health Perception, Role Physical, Role Emotional, Social Functioning, and Mental Health). Responses to the questions were graded on a numerical scale, with 1 as the best score and higher numbers as worse scores. The raw scores from the subscales were converted and summed by the Investigator to a total score between 0 and 100 to measure functional health and well-being from the patient's point of view. The final score range was 0 (representing the lowest possible score; worst health state) to 100 (representing the highest possible score; best health state).
Time to First All-cause Non-elective Hospitalization [Baseline to Week 28]
The time to first all-cause nonelective hospitalization during the study period will be assessed.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Signed informed consent form.
At least 18 years of age.
Primary diagnosis of PAH .
Has had a diagnostic RHC performed at or within 3 years before Screening (or at Screening if one is not available) that is consistent with the diagnosis of PAH.
Has World Health Organization (WHO)/New York Heart Association (NYHA) Functional Class (FC) II to III symptoms
Must be on a stable dose of PAH-specific oral therapy, defined as no change in dose or regimen for at least 120 days prior to randomization. Allowable PAH-specific therapy is an endothelin receptor antagonist and/or a phosphodiesterase type 5 inhibitor (PDE5-I) or a soluble guanylate cyclase (sGC) stimulator. Subjects may be on a stable dose of either a PDE5-I or a sGC stimulator, not both.
Has a 6-minute walk distance (6MWD) of ≥150 meters at Screening.
Has a VE/VCO2 slope ≥38 during the Screening CPET, as assessed by the CPET core laboratory.
Has a peak VO2 of ≥10 to <18 mL·kg-1·min-1 during the Screening CPET, as assessed by the CPET core laboratory.
If the subject is taking concomitant medications that may affect the clinical manifestations of PAH, the subject must be on a stable dose for at least 30 days prior to randomization. The exception is that the dose of diuretics should remain stable for at least the 10 days prior to randomization and the dosage maintained throughout the study.
Both male and female subjects agree to use a highly effective method of birth control throughout the entire study period from informed consent through to the Week 28 Visit/28-day Follow-up Visit, if the possibility of conception exists. Eligible male and female subjects must also agree not to participate in a conception process during the study and for 30 days after the final dose of study drug. Eligible male subjects must agree not to participate in sperm donation for 90 days after the final dose of study drug.

Women who are surgically sterile or postmenopausal are not considered to be of childbearing potential. If of childbearing potential, female partners of male study participants should agree to utilize medically acceptable methods of contraception for the duration of study participation.

Exclusion Criteria:

For subjects with known human immunodeficiency virus-associated PAH, a cluster designation of differentiation 4 (CD4+) T-cell count <200/mm3 at Screening.
Has 3 or more left ventricular disease dysfunction risk factors.
Symptomatic coronary disease and/or myocardial infarction within past 6 months.
Current symptomatic aortic or mitral valve disease.
Has evidence of more than mild lung disease on pulmonary function tests performed within 1 year prior to, or during, Screening.
Has evidence of thromboembolic disease as determined by ventilation-perfusion lung scan or local standard of care diagnostic evaluation at or after diagnosis of PAH.
Current diagnosis of ongoing and clinically significant sleep apnea as defined by the Investigator.
Requires use of supplemental oxygen during CPET.
Respiratory exchange ratio <1.0 at Screening CPET as determined by the CPET core laboratory.
Acute non-cardiac disorder that may affect exercise performance or be aggravated by exercise (eg, infection, renal failure, thyrotoxicosis).
Male subjects with a QTcF >450 msec and female subjects with a QTcF >470 msec on electrocardiogram (ECG) recorded at Screening and analyzed by the central ECG laboratory. Subjects with evidence of intraventricular conduction delay, defined as a QRS interval >110 msec, will be excluded if QTcF is >500 msec for both males and females.
Severe chronic liver disease (ie, Child-Pugh Class C), portal hypertension, cirrhosis, or complications of cirrhosis/portal hypertension (eg, history of variceal hemorrhage, encephalopathy).
Confirmed active infection with hepatitis B virus or hepatitis C virus.
Subjects with alanine aminotransferase or aspartate aminotransferase ≥3 times the upper limit of normal or total bilirubin ≥2 times the upper limit of normal at Screening.
Chronic renal insufficiency as defined by an estimated glomerular filtration rate using the Modification of Diet in Renal Disease Study equation of <30 mL/min/1.73 m^2 or requiring dialysis at Screening.
Hemoglobin concentration <9 g/dL at Screening.
Subjects treated with an intravenous or subcutaneous prostacyclin pathway agent (eg, epoprostenol, treprostinil, or iloprost) for PAH at any time (use in vasoreactive testing is permitted).
Subjects currently on or who have been treated with an inhaled or oral prostacyclin pathway agent (iloprost, treprostinil, beraprost, or selexipag) within 120 days prior to randomization.
Subject has pulmonary veno-occlusive disease.
Malignancy diagnosed and/or treated within 3 years of Screening, with the exception of localized non-metastatic basal cell or squamous cell carcinoma of the skin or in-situ carcinoma of the cervix excised with curative intent.
Subject tests positive for amphetamine, cocaine, methamphetamine, methylenedioxymethamphetamine, or phencyclidine in urine drug screen performed at Screening, or has a recent history (6 months) of alcohol or drug abuse. Subjects will not be excluded due to a positive drug screen caused by prescribed medications.
Initiation or discontinuation of a cardio-pulmonary rehabilitation program based upon exercise within 90 days prior to Screening and/or planned during study participation.
Prior participation in any study of ralinepag or another interventional clinical study with medicinal products within 30 days prior to Screening. Concurrent participation in registry or observational studies is allowed, if the subject can fulfill all other entry criteria and comply with all study procedures.
Any reason that, in the opinion of the Investigator, precludes the subject from participating in the study (eg, any previous or intercurrent medical condition) that may increase the risk associated with study participation or that would confound study analysis (eg, right-to-left shunt detected during CPET) or impair study participation or cooperation.
Known hypersensitivity to ralinepag or any of the excipients.
Life expectancy <12 months based on the Investigator's opinion.
Women who are pregnant, lactating, or breast-feeding.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Banner University Medical Center (University of Arizona)	Tucson	Arizona	United States	85724
2	UCSD Medical Center (La Jolla)	La Jolla	California	United States	92037
3	University of Colorado Anschutz Medical Campus	Aurora	Colorado	United States	80045
4	National Jewish Health	Denver	Colorado	United States	80206
5	Tampa General Hospital/University of South Florida Center for Advanced Lung Disease and Lung Transplant	Tampa	Florida	United States	33606
6	Community Health Network	Indianapolis	Indiana	United States	46250
7	Tufts Medical Center	Boston	Massachusetts	United States	02111
8	New York Presbyterian Hospital	New York	New York	United States	10065
9	The Ohio State University Wexner Medical Center	Columbus	Ohio	United States	43210
10	Carilion Clinic Pulmonary and Sleep Medicine	Roanoke	Virginia	United States	24014
11	Hospital Britanico de Buenos Aires	Ciudad Autónoma de Bs. As.		Argentina	1280
12	Instituto de Cardiología de Corrientes	Corrientes		Argentina	W3400AMZ
13	Macquarie University	North Ryde	New South Wales	Australia	2109
14	Westmead Hospital, Dept Respiratory and Sleep Medicine	Westmead	New South Wales	Australia	2145
15	The Prince Charles Hospital	Chermside	Queensland	Australia	4032
16	Princess Alexandra Hospital	Woolloongabba	Queensland	Australia	4102
17	Ordensklinikum Linz GmbH, Elisabethinen	Linz		Austria	4020
18	AKH Wien, Innere Med. II, Kardiologie	Vienna		Austria	1090
19	Erasme University Hospital - Department of Cardiology	Brussels		Belgium	1070
20	Gasthuisberg University Hospital - Department of Pulmonology	Leuven		Belgium	3000
21	Hospital Madre Teresa	Belo Horizonte	MG	Brazil	30441-070
22	Hospital Sao Paulo	São Paulo	SP	Brazil	04037-002
23	Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina de São Paulo - InCor-HCFMUSP	São Paulo	SP	Brazil	05403-000
24	Centro de Hipertensão Pulmonar	Porto Alegre		Brazil	90035074
25	Peter Lougheed Center	Calgary	Alberta	Canada	T1Y 6J4
26	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
27	London Health Science Centre- Victoria Hospital	London	Ontario	Canada	N6A 5W9
28	Thoraxklinik-Heidelberg, Zentrum für Pulmonale Hypertonie	Heidelberg	Baden-Wurttemberg	Germany	69126
29	Universitätsklinikum Carl Gustav Carus TU Dresden, Medizinische Klinik I, Abteilung für Pneumologie	Dresden	Sachsen	Germany	01307
30	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano		Italy	20122
31	Centro Cardiologico Monzino, IRCCS	Milano		Italy	20138
32	AOU Policlinico Umberto I	Rome		Italy	00161
33	Uniwersytecki Szpital Kliniczny w Białymstoku, Klinika Kardiologii z Oddziałem Intensywnego Nadzoru Kardiologicznego	Białystok		Poland	15-276
34	Europejskie Centrum Zdrowia Otwock Szpital im. Fryderyka Chopina, Oddział Kardiologiczny	Otwock		Poland	05-400
35	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
36	Hospital Clínic I Provincial de Barcelona	Barcelona		Spain	08036
37	Hospital Universitario 12 de Octubre	Madrid		Spain	28041